Natural products have provided a wide range of biologically active agents, many of which have unique profiles of pharmacological activity and therapeutic potential. Over two hundred alkaloids have been identified in extracts from amphibian skins. These include batrachotoxins, which are potent activators of sodium channels, histrionicotoxins. which are noncompetitive blockers of nicotinic receptor channel complexes and of potassium channels, and pumiliotoxins, which have myotonic and cardiotonic activity due to inhibitory effects on closing of sodium channels. Pumiliotoxin B acts at a specific site on the sodium channel to increase sodium flux and augments the effects of other sodium channel agents, such as the scorpion toxins and brevetoxins. Structure activity relationships indicate a stereoselective interaction with the side chain hydroxy groups of the pumiliotoxin alkaloids. Local anesthetics inhibit the stimulatory effects of batrachotoxin on both sodium flux and phosphoinositide breakdown in brain synaptoneurosomes. In addition, local anesthetics stimulate incorporation of inositol into phosphoinositides. A 5-substituted- 8-methylindolizidine markedly enhances and then at higher concentrations inhibits binding of radioactive perhydrohistrionicotoxin to the nicotinic receptor-channel complex. It has agonist activity at nicotinic receptors of pheochromocytoma cells. Other dendrobatid alkaloids, such as both the cis- and trans-2,5-disubstituted decahydroquinolines, the 3,5-disubstituted indolizidines, the 2,5-disubstituted pyrrolidines, the 2,6- disubstituted piperidines and a 2,6-disubstituted-4- hydroxypiperidine are potent inhibitors of binding of perhydrohistrionicotoxin and have noncompetitive antagonist activity at nicotinic receptors of pheochromocytoma cells. The biological activity of trace alkaloids from dendrobatid frogs, such as the azatricyclododecenes, the amidines and the homopumiliotoxins, and of the tricyclic indole alkaloids from myobatrachid frogs remain unknown. One amidine alkaloid is a potent analgetic.